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Package leaflet:

Information for the user

Trisequens®

Film-coated tablets

Estradiol/norethisterone acetate

Read this entire leaflet carefully before you start taking this medicine because it contains important information for you.

-    Keep this leaflet. You may need to read it again.

-    If you have any further questions, ask your doctor or pharmacist.

-    This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.

8-2800-01-011-5

- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1.    What Trisequens® is and what it is used for

2.    What you need to know before you take Trisequens®

3.    How to take Trisequens®

4.    Possible side effects

5.    How to store Trisequens®

6.    Contents of the pack and other information

1. What Trisequens® is and what it is used for

Trisequens® is a sequential combined Hormone Replacement Therapy (HRT) which is taken every day without interruption. Trisequens® is used in postmenopausal women with at least 6 months since their last natural period.

Trisequens® contains 2 hormones, an oestrogen (estradiol) and a progestagen (norethisterone acetate). The estradiol in Trisequens® is identical to the estradiol produced in the ovaries of women, and is classified as a natural oestrogen. Norethisterone acetate is a synthetic progestagen, which acts in a similar manner as progesterone, another important female sex hormone.

Trisequens® is used for:

Relief of symptoms occurring after menopause

During the menopause, the amount of the oestrogen produced by a woman's body drops. This can cause symptoms such as hot face, neck and chest ('hot flushes'). Trisequens® alleviates these symptoms after menopause. You will only be prescribed Trisequens® if your symptoms seriously hinder your daily life.

Prevention of osteoporosis

After the menopause some women may develop fragile bones (osteoporosis). You should discuss all available options with your doctor.

If you are at an increased risk of fractures due to osteoporosis and other medicines are not suitable for you, you can use Trisequens® to prevent osteoporosis after menopause. The experience of treating women older than 65 years is limited.

2. What you need to know before you take Trisequens®

Medical history and regular check-ups

The use of HRT carries risks which need to be considered when deciding whether to start taking it, or whether to carry on taking it.

The experience in treating women with a premature menopause (due to ovarian failure or surgery) is limited. If you have a premature menopause, the risks of using HRT may be different. Please talk to your doctor.

Before you start (or restart) HRT, your doctor will ask about your own and your family's medical history. Your doctor may decide to perform a physical examination. This may include an examination of your breasts and/or an internal examination, if necessary.

Once you have started on Trisequens®, you should see your doctor for regular check-ups (at least once a year). At these checkups, discuss with your doctor the benefits and risks of continuing with Trisequens®.

Go for regular breast screening, as recommended by your doctor.

Do not take Trisequens®

If any of the following applies to you. If you are not sure about any of the points below, talk to your doctor before taking Trisequens®. Do not take Trisequens®:

• if you have, have had or suspect having breast cancer

•    if you have, have had or suspect having cancer of the womb lining (endometrial cancer) or any other oestrogen dependent cancer

•    if you have any unexplained vaginal bleeding

•    if you have excessive thickening of the womb lining (endometrial hyperplasia) that is not being treated

•    if you have or have ever had

a blood clot in a vein (venous thromboembolism), such as in the legs (deep venous thrombosis) or the lungs (pulmonary embolism)

•    if you have a blood clotting disorder (such as protein C, protein S or antithrombin deficiency)

•    if you have or previously have had a disease caused by blood clots in the arteries, such as

a heart attack, stroke or angina

•    if you have or have ever had a liver disease and your liver

function tests have not returned to normal

•    if you are allergic (hypersensitive) to estradiol, norethisterone acetate or any of the other ingredients of Trisequens® (listed in section 6 Contents of the pack and other information)

•    if you have a rare blood problem called 'porphyria' which is passed down in families (inherited).

If any of the above conditions appear for the first time while taking Trisequens®, stop taking it at once and consult your doctor immediately.

Warnings and precautions

Tell your doctor if you have ever had any of the following problems, before you start the treatment, as these may return or become worse during treatment with Trisequens®. If so, you should see your doctor more often for check-ups:

•    fibroids inside your womb

•    growth of womb lining outside your womb (endometriosis) or a history of excessive growth of the womb lining (endometrial hyperplasia)

•    increased risk of developing blood clots (see Blood clots in

a vein (venous thromboembolism))

•    increased risk of getting an oestrogen-sensitive cancer (such as having a mother, sister or grandmother who has had breast cancer)

•    high blood pressure

•    a liver disorder, such as a benign liver tumour

•    diabetes

•    gallstones

•    migraine or severe headaches

•    a disease of the immune system that affects many organs of the body (systemic lupus erythematosus, SLE)

•    epilepsy

•    asthma

•    a disease affecting the eardrum and hearing (otosclerosis)

•    a very high level of fat in your blood (triglycerides)

•    fluid retention due to cardiac or kidney problems

•    lactose intolerance.

Stop taking Trisequens® and see

a doctor immediately

If you notice any of the following

when taking HRT:

•    any of the conditions mentioned in the Do not take Trisequens® section

•    yellowing of your skin or the whites of your eyes (jaundice). These may be signs of a liver disease

•    a large rise in your blood pressure (symptoms may be headache, tiredness and dizziness)

•    migraine-like headaches which happen for the first time

•    if you become pregnant

• if you notice signs of a blood clot, such as:

-    painful swelling and redness of the legs

-    sudden chest pain

-    difficulty in breathing.

For more information, see Blood clots in a vein (venous thromboembolism).

Note: Trisequens® is not a contraceptive. If it is less than 12 months since your last menstrual period or you are under 50 years old, you may still need to use additional contraception to prevent pregnancy. Speak to your doctor for advice.

HRT and cancer

Excessive thickening of the lining of the womb (endometrial hyperplasia) and cancer of the lining of the womb (endometrial cancer)

Taking oestrogen-only HRT will increase the risk of excessive

thickening of the lining of the womb (endometrial hyperplasia) and cancer of the womb lining (endometrial cancer).

The progestagen in Trisequens® protects you from this extra risk.

Compare

In women who still have a womb and who are not taking HRT, on average, 5 in 1,000 will be diagnosed with endometrial cancer between the ages of 50 and 65.

For women aged 50 to 65 who still have a womb and who take oestrogen-only HRT, between 10 and 60 women in 1,000 will be diagnosed with endometrial cancer (i.e. between 5 and 55 extra cases), depending on the dose and for how long it is taken.

Unexpected bleeding

You will have a bleed once a month (so-called withdrawal bleed) while

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taking Trisequens®. But if you have unexpected bleeding or drops of blood (spotting) besides your monthly bleeding which:

•    carries on for more than the first 6 months

•    starts after you have been taking Trisequens® more than 6 months

•    carries on after you have stopped taking Trisequens®

see your doctor as soon as possible. Breast cancer

Evidence suggests that taking combined oestrogen-progestagen and possibly also oestrogen-only HRT increases the risk of breast cancer. The extra risk depends on how long you take hRt. The additional risk becomes clear within a few years. However, it returns to normal within a few years (at most 5) after stopping treatment.

Compare

Women aged 50 to 79 who are not taking HRT, on average, 9 to 17 in 1,000 will be diagnosed with breast cancer over a 5-year period.

For women aged 50 to 79 who are taking oestrogen-progestagen HRT over 5 years, there will be 13 to 23 cases in 1,000 users (i.e. an extra 4 to 6 cases).

Regularly check your breasts. See your doctor if you notice any changes such as:

•    dimpling of the skin

•    changes in the nipple

•    any lumps you can see or feel. Additionally, you are advised to join mammography screening programs when offered to you. For mammogram screening, it is important that you inform the nurse/healthcare professional who is actually taking the x-ray that you use HRT, as this

medication may increase the density of your breasts which may affect the outcome of the mammogram. Where the density of the breast is increased, mammography may not detect all lumps.

Ovarian cancer

Ovarian cancer is rare - much rarer than breast cancer. The use of oestrogen-only or combined oestrogen-progestagen HRT has been associated with a slightly increased risk of ovarian cancer.

The risk of ovarian cancer varies with age. For example, in women aged 50 to 54 who are not taking HRT, about 2 women in 2,000 will be diagnosed with ovarian cancer over a 5-year period. For women who have been taking HRT for 5 years, there will be about 3 cases per 2,000 users (i.e. about 1 extra case).

Effect of HRT on heart and circulation

Blood clots in a vein (venous thromboembolism)

The risk of blood clots in the veins is about 1.3 to 3 times higher in HRT users than in non-users, especially during the first year of taking it.

Blood clots can be serious, and if one travels to the lungs, it can cause chest pain, breathlessness, fainting or even death.

You are more likely to get a blood clot in your veins as you get older and if any of the following applies to you. Inform your doctor if any of these situations applies to you:

•    you are unable to walk for a long time because of major surgery, injury or illness (see section 3, If you need to have surgery)

•    you are seriously overweight (BMI > 30 kg/m²)

•    you have any blood clotting problem that needs long-term

treatment with a medicine used to prevent blood clots

•    if any of your close relatives has ever had a blood clot in the leg, lung or another organ

•    you have systemic lupus erythematosus (SLE)

•    you have cancer.

For signs of a blood clot, see Stop taking Trisequens® and see a doctor immediately.

Compare

Looking at women in their 50s who are not taking HRT, on average, over a 5-year period, 4 to 7 in 1,000 would be expected to get a blood clot in a vein.

For women in their 50s who have been taking oestrogen-progestagen HRT for over 5 years, there will be 9 to 12 cases in 1,000 users (i.e. an extra 5 cases).

Heart disease (heart attack)

There is no evidence that HRT will prevent a heart attack.

Women over the age of 60 years who use oestrogen-progestagen HRT are slightly more likely to develop heart disease than those not taking any HRT.

Stroke

The risk of getting stroke is about 1.5 times higher in HRT users than in non-users. The number of extra cases of stroke due to use of HRT will increase with age.

Compare

Looking at women in their 50s who are not taking HRT, on average, 8 in 1,000 would be expected to have a stroke over a 5-year period.

For women in their 50s who are taking HRT, there will be 11 cases in 1,000 users over 5 years (i.e. an extra 3 cases).

Other conditions

HRT will not prevent memory loss. There is some evidence of a higher risk of memory loss in women who

start using HRT after the age of 65. Speak to your doctor for advice.

Using other medicines

Some medicines may interfere with the effect of Trisequens®. This might lead to irregular bleeding. This applies to the following medicines:

•    Medicines for epilepsy (such as phenobarbital, phenytoin and carbamazepine)

•    Medicines for tuberculosis (such as rifampicin and rifabutin)

•    Medicines for HIV infection (such as nevirapine, efavirenz, ritonavir and nelfinavir)

•    Medicines for hepatitis C infections (such as telaprevir)

•    Herbal remedies containing St John's Wort (Hypericum perforatum).

Other medicines may increase the effects of Trisequens®:

•    Medicines containing ketoconazole (a fungicide).

Trisequens® may have an impact on a concomitant treatment with cyclosporine.

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines including medicines obtained without a prescription, herbal medicines or other natural products.

Laboratory tests

If you need a blood test, tell your doctor or the laboratory staff that you are taking Trisequens®, because this medicine can affect the results of some tests.

Taking Trisequens® with food and drink

The tablets can be taken with or without food and drink.

Pregnancy and breast-feeding Pregnancy: Trisequens® is for use in postmenopausal women only. If you become pregnant, stop taking Trisequens® and contact your doctor.

Breast-feeding: You should not take Trisequens® if you are breast-feeding.

Driving and using machines

Trisequens® has no known effect on the ability to drive or use machines.

Important information about some of the ingredients in Trisequens®

Trisequens® contains lactose monohydrate. If you have an intolerance to some sugars, contact your doctor before taking Trisequens®.

3. How to take Trisequens®

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are unsure.

If you are not switching from another hormone replacement therapy, you can start treatment with Trisequens® on any convenient day. If you are switching from another hormone replacement